Value and safety of steroids in treating ear disease.During this session, formal presentations were made by Dr. Rutka, Prof. Deitmer, and Dr. Dohar. These presentations were followed by a general discussion.
John Rutka, MD, FRCSC FRCSC Fellow of the Royal College of Surgeons of Canada
It appears to me that steroids are a very important component in resolving otic inflammation and infection more rapidly. However, the world literature provides conflicting messages as to their potential toxicity. Some animal studies have indicated that steroids might be toxic to the inner ear. (1-3) On the other hand, Parnes et al have been using high-dose dexamethasone--up to 30 and 40 mg/ ml--in humans for the treatment of Cogan's syndrome and sudden autoimmune sensorineural hearing loss Sensorineural hearing loss
Hearing loss caused by damage to the nerves or parts of the inner ear governing the sense of hearing.
Mentioned in: Tinnitus
sensorineural hearing loss , and their results suggest that steroids are not toxic. (4)
Steroids probably are not ototoxic ototoxic /oto·tox·ic/ (o´to-tok?sik) having a deleterious effect upon the eighth nerve or on the organs of hearing and balance.
adj. . I am concerned that they might prevent a perforation from healing, especially in an acute situation. But otherwise, I favor their concomitant use with a topical antibiotic.
I suspect that steroids provide an additive effect, particularly in patients with significant inflammation. For example, granulation tissue can "hide" bacteria. By reducing the inflammatory response, steroids allow for greater penetration of the antibiotic. A steroid might also minimize the risk of an allergic or irritative ir·ri·ta·tive
Adj. 1. irritative - (used of physical stimuli) serving to stimulate or excite; "an irritative agent"
irritating reaction to the antibiotic. In fact, in some studies, steroids alone appeared to be just as effective as antibiotics in treating acute external otitis otitis
Inflammation of the ear. Otitis externa is dermatitis, usually bacterial, of the auditory canal and sometimes the external ear. It can cause a foul discharge, pain, fever, and sporadic deafness. . (5-7)
Steroids might have other advantages, as well, in terms of reducing mucosal edema edema (ĭdē`mə), abnormal accumulation of fluid in the body tissues or in the body cavities causing swelling or distention of the affected parts. and thereby improving the delivery of drugs into the middle ear. In a Turkish study of chronic suppurative suppurative
pertaining to or emanating from suppuration; pus in e.g. suppurative arthritis, bronchopneumonia. otitis media (CSOM CSOM Carlson School of Management (University of Minnesota, Twin Cities)
CSOM Center for Sex Offender Management
CSOM Computer System Operator's Manual
CSOM Chronic Serous Otitis Media (middle ear infection) ), Kaygusuz et al found that the addition of dexamethasone dexamethasone /dex·a·meth·a·sone/ (dek?sah-meth´ah-son) a synthetic glucocorticoid used primarily as an antiinflammatory in various conditions, including collagen diseases and allergic states; it is the basis of a screening test in the to ciprofloxacin ciprofloxacin /cip·ro·flox·a·cin/ (sip?ro-flok´sah-sin) a synthetic antibacterial effective against many gram-positive and gram-negative bacteria; used as the hydrochloride salt.
n. shortened the required treatment course from 14 to 7 days. (8) The addition of dexamethasone also increased the rates of clinical response to both ciprofloxacin (from 80 to 90%) and tobramycin tobramycin /to·bra·my·cin/ (to?brah-mi´sin) an aminoglycoside antibiotic derived from a complex produced by Streptomyces tenebrarius, (from 70 to 75%), although these improvements were not statistically significant. On the other hand, some studies suggest that steroids do not have any such effect. Regardless, no study has shown that the addition of a steroid to an antibiotic increases the length of treatment.
With respect to the differences among individual steroids in the ear, little has been determined as to whether some are more effective than others or if high-potency steroids are more effective than low-potency agents. In a rat model, Emgard and Hellstrom recently demonstrated that betamethasone betamethasone /be·ta·meth·a·sone/ (ba?tah-meth´ah-son) a synthetic glucocorticoid, the most active of the antiinflammatory steroids; used topically as the benzoate, dipropionate, or valerate salts as an antiinflammatory, topically or dipropionate alone healed experimentally induced external otitis more rapidly than did hydrocortisone/oxytetracycline, with or without polymyxin B. (9)
Thomas Deitmer, MD, PhD
I would like to continue by reviewing a few other human and animal studies on the effects of ototopical steroids in various capacities.
Pharmacokinetics. In a study that Dr. Rutka referred to earlier, Parries et al conducted a two-part examination of steroid use--one in animals and one in humans. (4) In an examination of the pharmacokinetic profiles of hydrocortisone hydrocortisone (hī'drəkôr`tĭzōn'), another name for the steroid hormone cortisol, more especially used to refer to preparations of this hormone used medicinally. , methylprednisolone methylprednisolone /meth·yl·pred·nis·o·lone/ (-pred-nis´ah-lon) a synthetic glucocorticoid derived from progesterone, used in replacement therapy for adrenocortical insufficiency and as an antiinflammatory and immunosuppressant; also , and dexamethasone in cochlear cochlear
pertaining to or emanating from the cochlea.
the coiled portion of the membranous labyrinth located inside the cochlea; contains endolymph.
see Table 14. fluid, they used a guinea pig model to compare three routes of administration--intratympanic, oral, and intravenous. All three steroids achieved their highest degree of penetration into cochlear fluid via the topical route. The best profile was seen with methylprednisolone. The authors noted that not only is intratympanic administration more efficacious, but it also obviates the adverse effects seen with systemic administration.
Sensorineural hearing loss. Next, Parnes et al administered either dexamethasone (n = 20) or methylprednisolone (n = 17) intratympanically to 37 humans with sensorineural hearing loss that had been caused by various inner ear diseases. Patients who bad had immune-mediated hearing losses experienced the best response; notable improvement was also seen in several cases of sudden hearing loss. On the other hand, no benefit occurred in patients who had had a sudden deterioration of pre-existing hearing loss or those with cochlear hydrops. No patient experienced treatment-induced hearing loss or eardrum ear·drum
The thin, semitransparent, oval-shaped membrane that separates the middle ear from the external ear. Also called drum, drumhead, drum membrane, myringa, myrinx, tympanic membrane, perforation. Transient treatment-related otitis media occurred in three patients, but it was controlled with antibiotic therapy. The authors concluded that topical injection of steroids appears to be safe and effective in certain diseases.
Refractory otitis externa. In a study of 13 patients with refractory chronic otitis externa chronic otitis externa Otitis externa ENT A condition of young adults, characterized by inflammation, irritation or infection of the external auditory canal, caused by mechanical trauma or chemical irritation. Cf Otitis media. , Stuck et al injected triamcinolone triamcinolone /tri·am·cin·o·lone/ (tri?am-sin´o-lon) a synthetic glucocorticoid used in replacement therapy for adrenocortical insufficiency and as an antiinflammatory and immunosuppressant in a wide variety of disorders. directly into the skin of the meatus. (10) Most patients experienced a complete cure, and the remainder improved substantially.
Prevention of PTTO. Possible ototoxicity Ototoxicity Definition
Ototoxicity is damage to the hearing or balance functions of the ear by drugs or chemicals.
Ototoxicity is drug or chemical damage to the inner ear. was a concern for Morpeth et al in their comparison of ciprofloxacin and an antibiotic/steroid combination for the prevention of post-tympanostomy tube otorrhea (PTTO). (11) In a randomized ran·dom·ize
tr.v. ran·dom·ized, ran·dom·iz·ing, ran·dom·iz·es
To make random in arrangement, especially in order to control the variables in an experiment. , double-blind trial, they administered either topical ciprofloxacin or topical neomycin/polymyxin B/ hydrocortisone to 100 children (200 ears)--aged 7 months to 11 years--who had undergone myringotomy myringotomy /my·rin·got·o·my/ (mi-ring-got´ah-me) tympanotomy; creation of a hole in the tympanic membrane, as for tympanocentesis.
n. and tube placement for the treatment of chronic or recurrent otitis media. Patients received 3 drops of medication three times daily for 3 days, beginning at the time of tube placement. At the 3-week follow-up, there was no significant difference in the rates of PTTO in the two groups. The authors therefore recommended ciprofloxacin for the prevention of PTTO, because its use obviates the risk of ototoxicity without sacrificing efficacy.
Acute otitis media Acute otitis media
Inflammation of the middle ear with signs of infection lasting less than three months.
Mentioned in: Myringotomy and Ear Tubes
acute otitis media . In an animal experiment, dexamethasone was studied as an adjunct to penicillin G in preventing mucosal changes during experimentally induced acute otitis media in 27 rats. (12) After all animals were inoculated with Streptococcus pneumoniae, nine were treated with penicillin alone, nine received penicillin/dexamethasone, and nine went untreated. Compared with the controls, structural changes were less evident in the two active-treatment groups, but more so in the antibiotic/steroid group, particularly with respect to mucosal metaplasia metaplasia /meta·pla·sia/ (met?ah-pla´zhah) the change in the type of adult cells in a tissue to a form abnormal for that tissue. to the secretory epithelium.
Gelfoam-induced adverse events. In another animal experiment, hydrocortisone ointment was studied to determine if it could reduce the adverse effects of Gelfoam on an abraded middle ear cavity--specifically, if it could prevent the development of connective tissue. (13) Twenty rats were divided into two groups; the middle ear mucosa was abraded in 10 rats and left intact in the other 10. Both groups were further subdivided; half of each group had Gelfoam alone inserted into the middle ear cavity and the other half received Gelfoam plus the steroid. At the 8-week evaluation, the abraded ears that received the steroid manifested significantly less Gelfoam-induced fibroblastic activity, vascular proliferation, and mild to moderate fibrosis than did the abraded ears that received Gelfoam alone. Likewise, the benefit of the steroid was noted in the intact ears, although not to as great an extent.
Joseph E. Dohar, MD, MS, FAAP FAAP Fundação Armando Álvares Penteado (University from São Paulo - Brazil)
FAAP Fellow of the American Academy of Pediatrics
FAAP Framework for African Agricultural Productivity
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FAAP Federal-Aid Airport Program , FACS FACS Fellow of the American College of Surgeons.
Fellow of the American College of Surgeons
fluorescence-activated cell sorter.
At the Children's Hospital of Pittsburgh, we conducted a randomized, blinded, placebo-controlled experiment to assess the efficacy of an antibiotic (tobramycin) and a steroid (dexamethasone), alone and in combination, in 60 juvenile cynomolgus monkeys with CSOM. (14) CSOM had been established by creating a large perforation in the right ear of each animal and inoculating it with Pseudomonas aeruginosa. The ears were allowed to drain for 4 weeks, and then the animals were administered one of six types of eardrop (10 monkeys in each group): 0.3% tobramycin alone, 0.1% dexamethasone alone, low-strength combination tobramycin/dexamethasone (0.3/0.1%), high-strength tobramycin/dexamethasone (1.0/0.33%), vehicle only, or phosphate-buffered saline. Each subject received 3 drops twice daily for 7 weeks.
By the end of treatment, all of the antibiotic groups had experienced a rapid resolution of otorrhea and eradication of P aeruginosa, but the most effective treatments were the two antibiotic/steroid combinations. In the dexamethasone-only group, the vehicle group, and the saline group, otorrhea and positive cultures persisted. The superiority of the antibiotic/steroid combinations was unequivocal. An interesting finding was that although the tobramycin-only group experienced a longer duration of otorrhea than did the combination groups, no P aeruginosa was present in the discharge. I believe this represents common-sense evidence that a combination agent successfully treats both the infectious and the inflammatory components of CSOM.
We used the same basic study design to compare ciprofloxacin/hydrocortisone with ciprofloxacin alone, but we did not find any difference between the two active regimens. We speculate that the reason for the lack of a difference was our use of hydrocortisone, which is less potent than dexamethasone. An interesting facet of this study concerned the healing of the tympanic membrane. Monkeys have extremely small external auditory canals and eardrums. Even after a complete perforation, the drums will often close, which was problematic during this study. When closures occurred, we had to reperforate the drum, and when we found sterile effusion effusion /ef·fu·sion/ (e-fu´zhun)
1. escape of a fluid into a part; exudation or transudation.
2. effused material; an exudate or transudate. or no effusion, we had to reinoculate the ear with P aeruginosa. We discovered during this process that the eardrums that had the highest closure rates were those that had been treated with either ciprofloxacin/hydrocortisone or ciprofloxacin alone, as opposed to vehicle or saline. Approximately 50% of the perforations that were treated with either active agent had closed. Therefore, we realized that the antibiotic made an obvious contribution to the resolution of both the infectious and inflammatory processes and allowed the eardrums to heal.
Dr. Roland: As we've heard in these three presentations, steroids appear to have an additive effect when used with an antibiotic to treat otorrhea. By what mechanism does this effect occur?
Dr. Dohar: Even after antibiotic monotherapy eradicates the pathogen, there is a time lag before the body can reverse the mucosal inflammatory changes. The addition of a steroid expedites the resolution of the inflammatory process, which follows a separate, and in some ways independent, time course. We have conducted chinchilla chinchilla (chĭnchĭl`ə), small burrowing rodent of South America. It lives in colonies at high altitudes (up to 15,000 ft/4,270 m) in the Andes of Bolivia, Chile, and Peru. studies to look at cytokine expression and certain key inflammatory mediators for otitis media. We found that even down at the molecular level, the addition of a steroid resulted in a very dramatic and rapid decrease in the expression of these mediators, regardless of whether we used a concomitant antibiotic or not. We feel fairly certain from these data that this is the mechanism by which steroids help.
Dr. Roland: According to the available animal data, it also appears that steroids cause little or no ototoxicity. However, the low pH levels of the solutions in which they are usually delivered might lead to some ototoxicity. For example, acetic acid is ototoxic. Of course, a steroid cannot be kept in suspension except at a fairly low pH level, say less than 5.5. One reason that tobramycin/ dexamethasone is so attractive is that it's a microsuspension rather than a macrosuspension. It looks like a solution but it actually isn't.
Dr. Conroy: That's true in general. There are some formulation changes that we can make that will keep a steroid a solution. The problem is that these solutions are less stable at higher pH levels. The pH levels of ciprofloxacin/hydrocortisone and ciprofloxacin/dexamethasone range between 4 and 5. At any pH level beyond 5.5, not only does the steroid become less capable of remaining in suspension, but the antibiotic does also.
Dr. Rutka: As mentioned earlier, Parnes et al used high-dose dexamethasone for the treatment of Cogan's syndrome and post-traumatic sensorineural hearing loss, and it did not cause any significant harm to the inner ear. (4) However, it is difficult to know whether some of the post-trauma patients would have improved spontaneously given time.
Anecdotally, approximately 40% of our patients in Toronto who underwent topical gentamicin/betamethasone ablation for the treatment of incapacitating in·ca·pac·i·tate
tr.v. in·ca·pac·i·tat·ed, in·ca·pac·i·tat·ing, in·ca·pac·i·tates
1. To deprive of strength or ability; disable.
2. To make legally ineligible; disqualify. Meniere's disease continued to have a small tympanic membrane perforation tympanic membrane perforation Perforated, punctured, ruptured ear drum ENT A disruption of the tympanic membrane due to acoustic trauma, direct injury, barotrauma, introduction of Q-tips or small objects, or infection with fluid buildup in the middle ear. See Tympanoplasty. following extrusion of their tubes (see page 9). One can speculate that the long-term use of the antibiotic/steroid combination might have prevented these eardrums from healing by reducing the inflammatory response and thereby allowing the skin edges of the perforation to meet with the mucosal edges. All of this was on a backdrop of our use of concentrated phenol as the topical anesthetic during tube insertion.
Finally, it appears reasonable to conclude that steroids significantly reduce pain in patients with external otitis, especially considering what we know to be the histopathology his·to·pa·thol·o·gy
The science concerned with the cytologic and histologic structure of abnormal or diseased tissue.
The study of diseased tissues at a minute (microscopic) level. in this condition.
Dr. Roland: There is a meaningful degree of systemic absorption of topical dexamethasone via the middle ear mucosa. Should we be concerned about adrenal-pituitary axis suppression?
Dr. Dohar: From an immunosuppression immunosuppression
Suppression of immunity with drugs, usually to prevent rejection of an organ transplant. Its aim is to allow the recipient to accept the organ permanently with no unpleasant side effects. standpoint, absorption is a nonissue non·is·sue
A matter of so little import that it ought not to become a focus of controversy and comment: She felt that the matter of her attire should have been a nonissue. in adults. Is there any gross suppression in children? Probably not, provided that therapy is only short term. We have seen some suppression in children who took long-term inhalational steroids for allergic rhinitis or asthma. But for short-term treatment of ear disease, we shouldn't worry because the serum steroid levels are quite low.
Dr. Roland: But if it turns out that a child has taken a steroid-containing drop for 3 or 4 months, some adrenal adrenal /ad·re·nal/ (ah-dre´n'l)
2. adrenal gland.
3. pertaining to an adrenal gland.
1. suppression could occur. Should we be concerned that such a drug is on the market?
Prof. Hawke: There isn't any drug on the market that will not cause damage if it's used improperly. So, no, I'm not worried about the fact that the drug is available. I'm just worried about patients who abuse medications because they think, "If a little works, a lot must work faster. If short-term is good, long-term must be better."
Dr. Dohar: Yes, but a patient won't have a 3-month supply if a physician doesn't write a prescription for it. So the physician can prevent this problem. That's not a concern for me.
Dr. Conroy: Systemic absorption of potent steroids is clearly something we should be concerned about. The pharmacokinetic data we've obtained thus far on ciprofloxacin/dexamethasone indicates that there is systemic absorption, but not to the degree that it would cause cortisol cortisol (kôr`tĭsôl') or hydrocortisone, steroid hormone that in humans is the major circulating hormone of the cortex, or outer layer, of the adrenal gland. suppression, at least not with short-term dosing. However, no one knows what would happen if pain were to persist and the patient were to take the drops for a much longer period. It's always possible that a patient will abuse a drug, and we certainly have very little control over that once the patient leaves the pharmacy. But we can take precautions in formulating drugs, which we have done with ciprofloxacin/dexamethasone. After a 7-day course of treatment, we would not expect to see anything even close to clinically relevant cortisol suppression. Our data show that the level of cortisol suppression with topical ciprofloxacin/dexamethasone is 7-fold lower than that seen with a single 0.5-mg dose of oral dexamethasone. Even if a patient took topical ciprofloxacin/dexamethasone for a month, cortisol suppression would probably be minimal and quite reversible.
Dr. Roland: Would a nonsteroidal anti-inflammatory drug nonsteroidal anti-inflammatory drug, a drug that suppresses inflammation in a manner similar to steroids, but without the side effects of steroids; commonly referred to by the acronym NSAID (ĕn`sĕd). (NSAID NSAID: see nonsteroidal anti-inflammatory drug. ) be as good as or better than a steroid in combination with an antibiotic? Should such a product be developed?
Dr. Rutka: I am not aware of any topical NSAID, but oral NSAIDs have been an invaluable adjunct in the management of pain in patients with necrotizing necrotizing /nec·ro·tiz·ing/ (nek´ro-tiz?ing) causing necrosis.
Causing the death of a specific area of tissue. Human bites frequently cause necrotizing infections. external otitis.
Prof. Deitmer: I know from performing general surgery that NSAIDs are effective in diseases that are close to the skin. Perhaps we should consider using an NSAID.
Dr. Dohar: In our animal studies of inflammatory middle ear disease, we found that steroids do exert a very short-rived suppressive sup·pres·sive
Tending or serving to suppress.
Adj. 1. suppressive - tending to suppress; "the government used suppressive measures to control the protest" effect on local immunity expression; IgA secretion was the most significant. In humans, this is usually not clinically significant. But there is a small subset of patients in whom it might be significant. In these patients, an NSAID would probably be a better option.
Dr. Roland: Are high-potency steroids more effective than low-potency steroids?
Dr. Dohar: First, I have come to learn that otolaryngologists' perceptions of steroid potency are completely different from rheumatologists' perceptions. They consider dexamethasone to be in the same category of low potency as hydrocortisone. We have the perception that there are distinct differences between the two steroids. Actually, it's not just a perception; it's backed up by evidence from our animal studies.
Second, we can always achieve whatever degree of anti-inflammatory activity we wish by simply adjusting the dosing regimen. For example, we can increase the potency of dexamethasone by applying it directly to tissue with an otowick. Because the steroid remains in contact with the tissue longer, its anti-inflammatory effects last longer. Our studies of inflammatory markers confirm this.
Dr. Roland: You're right. The rank order of steroid potency in the eye is different from the rank order of potency in the skin. No one knows what the rank order of potency in the ear is. But it's certainly true that the switch from dexamethasone to mometasone, fluticasone, and triamcinolone made a big difference in nasal sprays. I realize that ciprofloxacin/dexamethasone is recommended for short- rather than long-term use, but I'm not so sure that this really is a nonissue.
Dr. Conroy: In well-established ophthalmic models, cortisone cortisone (kôr`tĭsōn'), steroid hormone whose main physiological effect is on carbohydrate metabolism. It is synthesized from cholesterol in the outer layer, or cortex, of the adrenal gland under the stimulation of adrenocorticotropic and hydrocortisone-like steroids are usually ranked at the bottom of the potency list and dexamethasone at the top. Mometasone, fluticasone, and triamcinolone are somewhere in the middle. There are many other models we can use to rank relative potency, and rankings can vary according to organ system and mode of administration. Depending on what constraints we put on a model, we can achieve all kinds of different results. In the models that we used for post-tympanostomy tube acute otitis media with otorrhea and acute otitis externa, we found no better steroid than dexamethasone (see page 2).
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(2.) Spandow O, Anniko M, Hellstrom S. Hydrocortisone applied into the round window niche causes electrophysiological dysfunction of the inner ear. ORL ORL Oto-Rhino Laryngologie (France)
ORL Orlando Executive Airport (Airport Code)
ORL Optical Return Loss
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(3.) Spandow O. Are glucocorticoids Glucocorticoids
Any of a group of hormones (like cortisone) that influence many body functions and are widely used in medicine, such as for treatment of rheumatoid arthritis inflammation. in ear drops ototoxic? Acta Otolaryngol Suppl 1992;493:89-91.
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(Russian: “fist”) Wealthy or prosperous landed peasant in Russia. Before the Russian Revolution of 1917, kulaks were major figures in peasant villages, often lending money and playing central roles in social and administrative affairs. Burun Bogaz Ihtis Derg 2002;9:106-11.
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HNO Hals-Nasen-Ohren Heilkunde (German: throat, nose and ear medicine)
HNO Host Network Operator
HNO Harvard News Office
HNO Helvetica Narrow Oblique (font) 2001;49:199-203.
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(13.) Bahadir O, Aydin S, Caylan R. The effect on the middle-ear cavity of an absorbable gelatine sponge alone and with corticosteroids Corticosteroids Definition
Corticosteroids are group of natural and synthetic analogues of the hormones secreted by the hypothalamic-anterior pituitary-adrenocortical (HPA) axis, more commonly referred to as the pituitary gland. . Eur Arch Otorhinolaryngol 2003;260:19-23.
(14.) Alper CM, Dohar JE, Gulhan M, et al. Treatment of chronic suppurative otitis media with topical tobramycin and dexamethasone. Arch Otolaryngol Head Neck Surg 2000;126:165-73.